Inhibitory systems are important in maintaining proper levels of excitation in the brain, and are often disrupted following status epilepticus. The efficacy of synaptic inhibition, provided by inhibitory interneurons that release the neurotransmitter GABA, is maintained by the chloride- cation cotransporter KCC2. KCC2 pumps chloride ions in an outward direction, maintaining low concentrations of chloride inside neurons, allowing for hyperpolarization when chloride- permeable GABA receptors are activated. However, in the epileptic brain, chloride has been found to accumulate inside neurons, causing GABA to act in an excitatory fashion. Recent evidence indicates that a chloride gradient exists across the dendrites, somata, and axons. However, whether dendritic and axonal chloride are disrupted in the epileptic brain remain unknown. In addition, the molecular signaling pathways that underlie the shift in intracellular chloride have not been examined. In the proposed research, I will test the hypothesis that intracellular zinc mediates changes in the axo-dendritic chloride gradient following status epilepticus. PUBLIC HEALTH RELEVANCE: Epilepsy is an extremely common neurological disorder, with approximately 1% of the worldwide population afflicted at any given time. While pharmacological or surgical intervention can eliminate or reduce the incidence of seizures in many cases, effective treatments remain elusive for a significant number of patients with epilepsy. Gaining an improved understanding of the mechanistic underpinnings of epilepsy is crucial to the development of novel therapeutic approaches for seizures. An emerging idea in the epilepsy research field concerns dysregulation of chloride as a important factor in epilepsy. Proper regulation of chloride ions inside neurons is required for maintaining appropriate levels of inhibition in the brain. Both human and animal studies have pinpointed differential expression of chloride transporters in the epileptic brain. However, the specific ways in which chloride homeostasis is regulated in distinct compartments of neurons is not understood, and the ways in which this subcellular regulation might change in the epileptic brain is also unknown. Finally, the molecular mechanisms that govern chloride transporter expression, and thus chloride homeostasis, have not been identified. Importantly, identification of the molecular pathways required for dysregulation of chloride in the epileptic brain would provide novel therapeutic targets in the treatment of epilepsy. Reversing the alteration in chloride transport in the epileptic brain would restore the efficacy of synaptic inhibition, and may prove to be an effective strategy in treating epilepsy. For these reasons, the research proposed here has the potential to impact the lives of millions of patients with medically refractory epilepsy.